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In the past few years, several novel anticancer agents targeting protein kinases have been discovered expanding the available therapeutic arsenal. However, few new therapeutic approaches have been developed for the treatment of childhood cancer. To this end, we have been making efforts to contribute to this important field. Herein, we identified a series of new 4,6-disubstituted quinoline derivatives from our in-house quinoline chemical library that showed promising anti-proliferative activity against Ewing Sarcoma (ES). This interesting observation engaged us to further investigate these derivatives since this type of cancer is among the most common bone cancers in children. Evaluation of the quinoline derivatives against a panel of kinases demonstrated generally narrow selectivity profiles of this compound class. Interestingly, the main kinases that were inhibited belonged to the NAK family of kinases, in particular, the family member cyclin G-associated kinase (GAK) which was inhibited at nanomolar range in enzyme kinetic assays.